Abstract 286: Targeting metabolic vulnerabilities in acute myeloid leukemia
Authors: Kanwal Mahmood Hameed, Ashkan Emadi
Journal: Cancer Research (2023)

Abstract Glutamine (Gln) is the most abundant amino acid intracellularly and in the plasma. Importantly, Gln depletion has emerged as a therapeutic approach for cancers that have undergone metabolic reprogramming and have exhibited a dependence on Gln for survival, including acute myeloid leukemia (AML). Asparaginases are bacterial enzymes that hydrolyze plasma glutamine to glutamate and ammonia, depriving glutamine-dependent AML cells from one of their vital nutrients. Preliminary data and literature have shown that following treatment with asparaginases in vitro there is a consistent increase in serine (Ser). Therefore, we hypothesized that in response to Gln depletion, AML cells upregulate de novo Ser biosynthesis as a compensatory pathway, and the inhibition of this pathway will synergize with Gln depletion to increase cytotoxicity in AML cells. We will test this by targeting, phosphoglycerate dehydrogenase (PHGDH), a key enzyme in Ser biosynthesis, which is a very common target for serine biosynthesis. We determined that crisantaspase (Rylaze) inhibited the proliferation of several AML cell lines with pharmacologically relevant IC50 values. Similarly, decreasing the concentration of Gln in the media resulted in a dose-dependent decrease in the proliferation, growth, and expansion of AML cells, confirming AML sensitivity to Gln depletion. Protein expression of PHGDH and PSAT was upregulated following Gln withdrawal from the media as well as following crisantaspase treatment. We set out to explore the effects of PHGDH knockout and observed that the PHGDH knockout AML cells were significantly more sensitive to crisantaspase, yielding IC50 values ranging from, ~250-fold lower compared to the parental lines. Gln depletion through crisantaspase treatment or withdrawal from the media decreased GSH levels and increased LDH release, both of which were further enhanced by PHGDH knockout. Indicating enhanced oxidative stress and cytotoxicity when both Gln and Ser are targeting in combination. Additionally, silencing of PHGDH reinforced anti-leukemic effects of glutamine modulation by different glutamine metabolism inhibitors, including V9302, CB-839 and BPTES. Preliminary testing of an NAD-dependent cell permeable PHGDH competitive inhibitor prodrug (BI4916) demonstrated an inhibition of AML cell proliferation in multiple cell lines. It has also demonstrated potential synergism and increase in cellular cytotoxicity when used in combination with Rylaze. Simultaneous targeting of Ser and Gln metabolism for AML treatment shows promising results in vitro with great potential for translation into clinical practice with clinically available asparaginases, and other glutamine modulators. Ongoing work is focused on the design of a more potent pharmacologic inhibitor of PHGDH to combine with crisantaspase as a novel treatment approach for AML. Citation Format: Kanwal Mahmood Hameed, Ashkan Emadi. Targeting metabolic vulnerabilities in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 286.